1. Field of Invention
This invention provides compounds that inhibit protein kinases, prodrugs of the compounds, intermediates and methods of synthesizing the compounds and/or prodrugs, pharmaceutical compositions comprising the compounds and/or prodrugs and methods of using the compounds and/or prodrugs in a variety of contexts, including, for example, in the treatment and/or prevention of various diseases that are responsive to protein kinase inhibition and/or that are mediated, at least in part, by inappropriate kinase activity.
2. Description of Related Art
Protein Kinases
Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J., 9:576 596 (1995); Knighton et al., Science, 253:407 414 (1991); Hiles et al., Cell, 70:419 429 (1992); Kunz et al., Cell, 73:585 596 (1993); Garcia-Bustos et al., EMBO J., 13:2352 2361 (1994)).
In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor (α TNF-α)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
SYK Kinase
Spleen tyrosine kinase (Syk) is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses. Thus, Syk plays a pivotal role in signaling through the Fc receptor and integrins in both neutrophils and macrophages. Syk is also important for signaling of the high affinity IgE receptor, Fc εR1, in mast cells and in receptor antigen signaling in T and B lymphocytes. The signal transduction pathways present in phagocytes, mast, T and B cells have common features. The ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity. However, they interact with transducing subunits that contain immunoreceptor tyrosine based activation motifs (ITAMs) (M. Reth, Nature, 1989, 338, pages 383-384). These motifs are present in both the β and γ subunits of the Fc εR1, in the ξ-subunit the of T cell receptor (TCR) and in the IgGα and IgGβ subunits of the B cell receptor (BCR) (N. S. van Oers and A. Weiss, Seminars in Immunology, 1995, 7, pages 227-236). Upon binding of antigen and multimerization, the ITAM residues are phosphorylated by protein tyrosine kinases of the Src family. Syk belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2-mediated association of Syk with an activated receptor stimulates Syk kinase activity and localizes Syk to the plasma membrane.
In Syk deficient mice, mast cell degranulation is inhibited, suggesting that this is an important target for the development of mast cell stabilizing agents (P. S. Costello, Oncogene, 1996, 13, pages 2595-2605). Similar studies have demonstrated a critical role for Syk in BCR and TCR signaling (A. M. Cheng, Nature, 1995, 378, pages 303-306, (1995) and D. H. Chu et al., Immunological Reviews, 1998, 165, pages 167-180). Syk also appears to be involved in eosinophil survival in response to IL-5 and GM-CSF (S. Yousefi et al., J. Exp. Med., 1996, 183, pages 1407-1414). Despite the key role of Syk in mast cell, BCR and T cell signaling, little is known about the mechanism by which Syk transmits downstream effectors. Two adaptor proteins, BLNK (B cell Linker protein, SLP-65) and SLP-76 have been shown to be substrates of Syk in B cells and mast cells respectively and have been postulated to interface Syk with downstream effectors (M. Ishiai et al., Immunity, 1999, 10, pages 117-125 and L. R. Hendricks-Taylor et al., J. Biol. Chem, 1997, 272, pages 1363-1367). In addition Syk appears to play an important role in the CD40 signaling pathway, which plays an important role in B cell proliferation (M. Faris et al., J. Exp. Med., 1994, 179, pages 1923-1931).
Syk is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fcγ-RIIA) or stimulated by collagen (F. Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471-478).
Crosslinking of Fc receptors, such as the high affinity receptors for IgG, IgE (FcεRI), as well as stimulation through integrins, activates signaling cascades in immune cells that result in the activation of the cells and/or release of preformed mediators. These mediators include molecules such as histamine from mast cells and lactoferrin, catalase, and elastase from neutrophils via degranulation. It also leads to the synthesis and release of other mediators, including cytokines such as TNF alpha and IL 2 as well as nitric oxide, leukotrienes, prostaglandins and platelet-activating factors (PAFs), which play important roles in inflammatory reactions.
The signaling cascade(s) activated by crosslinking Fc receptors such as FcεRI and/or FcγRI comprises an array of cellular proteins. Among the most important intracellular signal propagators are the tyrosine kinases. And, an important tyrosine kinase involved in the signal transduction pathways associated with crosslinking the FcεRI and/or FcγRI receptors, as well as other signal transduction cascades, is Syk kinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):357-362 for review). The mediators released as a result of FcεRI and/or FcγRI receptor cross-linking are responsible for, or play important roles in, the manifestation of numerous events, some of which are adverse. Therefore, there exists a need for compounds which are able to effectively inhibit Syk kinase.
Kinase Diseases
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signal upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. However, considering the lack of currently available treatment options for the majority of the conditions associated with protein kinases, there is still a great need for new therapeutic agents that inhibit these protein targets.
All references cited herein are incorporated herein by reference in their entireties.